The approach to the patient with single and multiple liver metastases, pulmonary metastases, and intra-abdominal metastases from colorectal carcinoma

Recurrent colorectal carcinoma constitutes a major health care problem, with 90,000 patients diagnosed annually with metastatic disease. Recent advances have offered treatment to selected patients with liver, lung, and intra-abdominal metastases. Resection of liver secondary tumors improves 5-year survival from 0% to approximately 30% and offers the only possibility for cure. As experience mounts, hepatic surgery can be performed with quite acceptable morbidity and mortality. Adjuvant therapies are being developed that may improve results with surgery alone. Cryoablation is a new technique that appears to effectively eradicate liver tumors, but its role remains to be defined. In patients with unresectable disease, the benefit of hepatic artery infusion of chemotherapy is unproven. Resection of pulmonary metastases significantly improves survival in patients with solitary nodules. Consistent data regarding the benefit of pulmonary metastatectomy in patients with multiple nodules are not available. Combined cytoreductive surgery and intraperitoneal hyperthermic chemotherapy is being investigated as a treatment for peritoneal carcinomatosis from colorectal cancer. Although selected patients may benefit, this combined treatment modality appears to be less effective in patients with colorectal cancer than with other types of cancer.     

Transport of opioid peptides into the central nervous system

Peptide hormones and neurotransmitters play crucial roles in the maintenance of physiological function at both the cellular and organ level. Although peptide neuropharmaceuticals have enormous potential in the treatment of disease states, the blood-brain barrier (BBB) generally prevents the entry of peptides into the brain either by enzyme degradation or by specific properties of the BBB. Peptides that act at opioid receptors are currently being designed for analgesia and to reduce the unwanted side effects associated with morphine, such as addiction and inhibition of gastric motility. It has been the focus of our group to produce stabile peptide analogues of Met-enkephalin, that lead to analgesia without side effects. In this paper we present the methodologies that have been used to elucidate the transport mechanisms of three peptides across the BBB. Using a primary endothelial cell culture model of the BBB, in situ perfusion, and kinetic analysis we show that D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) crosses the BBB via diffusion, [D-penicillamine2,5]enkephalin uses a combination of diffusion and a saturable transport mechanism, and biphalin ([Tyr-D-Ala-Gly-Phe-NH]2) uses diffusion and the large neutral amino acid carrier. Understanding BBB transport mechanisms for peptides will aid in the rational design of peptides targeted to the brain.     

Inducible nitric oxide synthase expression is reduced in cystic fibrosis murine and human airway epithelial cells

It has been reported that exhaled nitric oxide levels are reduced in cystic fibrosis (CF) patients. We have examined the inducible isoform of nitric oxide synthase (iNOS) in the airways by immunostaining and found that iNOS is constitutively expressed in the airway epithelia of non-CF mouse and human tissues but essentially absent in the epithelium of CF airways. We explored potential consequences of lost iNOS expression and found that iNOS inhibition significantly increases mouse nasal trans-epithelial potential difference, and hindered the ability of excised mouse lungs to prevent growth of Pseudomonas aeruginosa. The absence of continuous nitric oxide production in epithelial cells of CF airways may play a role in two CF-associated characteristics: hyperabsorption of sodium and susceptibility to bacterial infections.     

X-ray crystal structure of glycinamide ribonucleotide synthetase from Escherichia coli

Glycinamide ribonucleotide synthetase (GAR-syn) catalyzes the second step of the de novo purine biosynthetic pathway; the conversion of phosphoribosylamine, glycine, and ATP to glycinamide ribonucleotide (GAR), ADP, and Pi. GAR-syn containing an N-terminal polyhistidine tag was expressed as the SeMet incorporated protein for crystallographic studies. In addition, the protein as isolated contains a Pro294Leu mutation. This protein was crystallized, and the structure solved using multiple-wavelength anomalous diffraction (MAD) phase determination and refined to 1.6 A resolution. GAR-syn adopts an alpha/beta structure that consists of four domains labeled N, A, B, and C. The N, A, and C domains are clustered to form a large central core structure whereas the smaller B domain is extended outward. Two hinge regions, which might readily facilitate interdomain movement, connect the B domain and the main core. A search of structural databases showed that the structure of GAR-syn is similar to D-alanine:D-alanine ligase, biotin carboxylase, and glutathione synthetase, despite low sequence similarity. These four enzymes all utilize similar ATP-dependent catalytic mechanisms even though they catalyze different chemical reactions. Another ATP-binding enzyme with low sequence similarity but unknown function, synapsin Ia, was also found to share high structural similarity with GAR-syn. Interestingly, the GAR-syn N domain shows similarity to the N-terminal region of glycinamide ribonucleotide transformylase and several dinucleotide-dependent dehydrogenases. Models of ADP and GAR binding were generated based on structure and sequence homology. On the basis of these models, the active site lies in a cleft between the large domain and the extended B domain. Most of the residues that facilitate ATP binding belong to the A or B domains. The N and C domains appear to be largely responsible for substrate specificity. The structure of GAR-syn allows modeling studies of possible channeling complexes with PPRP amidotransferase.     

The coordinator attrition problem in the United States: myth or reality?

A process of change was initiated in a Nicaraguan regional hospital in order to achieve a sustainable reduction of early neonatal mortality. A series of organizational, educational and hygienic measures was introduced, involving all staff in antenatal care, delivery care and neonatal care. Neonatal mortality decreased from 56/1000 live births in 1985 to 11/1000 in 1993. A commission of maternal and child health, a weekly perinatal audit, the active involvement of all staff and dedicated work of key individuals, as well as national policy decisions, are considered important determinants of the process. Keeping neonatal mortality in focus through continuous analysis of care routines, and through external exchange of ideas is important in order to sustain improvements and to decrease further the mortality.     

Occult bacteremia: is there a standard of care?

The evaluation and management of patients with occult bacteremia is controversial. The purpose of this study was to define the prevailing practices in the emergency management of occult bacteremia. Short, anonymous surveys were mailed to all 517 members of the Section on Emergency Medicine at the American Academy of Pediatrics. Three hundred six (59%) of those surveyed returned completed questionnaires. Eleven different temperature cutoff points are used, and 105 (34%) consider occult bacteremia in patients with temperature above 39 degrees C. Seventeen different age intervals are used to define the patients at risk for occult bacteremia, and the age range three to 24 months is used by 173 (57%) of those surveyed. Complete blood cell count is the most commonly used screening test; it is routinely ordered by 225 respondents (74%). One hundred thirty-seven participants (45%) routinely obtain blood cultures in all patients at risk for occult bacteremia, whereas 111 (36%) use the clinical appearance (toxicity) of the patient to determine whether a blood culture should be drawn. One hundred sixty-one (53%) of those surveyed routinely administer antibiotics to toxic-appearing patients pending the results of the blood culture. Laboratory criteria are used by 135 (44%) in the decision whether to administer empiric antibiotics. Ceftriaxone is the most commonly used antibiotic; it is routinely administered by 230 respondents (75%). Twenty participants (7%) routinely admit all patients with Streptococcus pneumoniae, whereas 217 (71%) admit all patients with Haemophilus influenzae bacteremia and 234 (76%) admit all patients with Neisseria meningitidis bacteremia. We conclude that diversity exists in the evaluation and management of occult bacteremia.